A Genome-Wide Association Study for Diabetic Retinopathy in a Japanese Population: Potential Association with a Long Intergenic Non-Coding RNA

Abstract

Elucidation of the genetic susceptibility factors for diabetic retinopathy (DR) is important to gain insight into the pathogenesis of DR, and may help to define genetic risk factors for this condition. In the present study, we conducted a three-stage genome-wide association study (GWAS) to identify DR susceptibility loci in Japanese patients, which comprised a total of 837 type 2 diabetes patients with DR (cases) and 1,149 without DR (controls). From the stage 1 genome-wide scan of 446 subjects (205 cases and 241 controls) on 614,216 SNPs, 249 SNPs were selected for the stage 2 replication in 623 subjects (335 cases and 288 controls). Eight SNPs were further followed up in a stage 3 study of 297 cases and 620 controls. The top signal from the present association analysis was rs9362054 in an intron of RP1-90L14.1 showing borderline genome-wide significance (Pmet = 1.4×10−7, meta-analysis of stage 1 and stage 2, allele model). RP1-90L14.1 is a long intergenic non-coding RNA (lincRNA) adjacent to KIAA1009/QN1/CEP162 gene; CEP162 plays a critical role in ciliary transition zone formation before ciliogenesis. The present study raises the possibility that the dysregulation of ciliary-associated genes plays a role in susceptibility to DR.

Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene

“…A study in a cohort of Taiwanese type 2 diabetes patients and a meta-analysis of Japanese patients identified several loci reaching significance, but these findings have not been validated in an independent cohort [18,19]. None of the top loci in these studies appear to be replicated by other studies.…”

“…We first assessed loci reported in previous GWAS of diabetic retinopathy [15][16][17][18][19] for association in the current study in an attempt to replicate previous findings. A p value of <0.002 was required to account for the 29 loci assessed.…”

“…Several other GWAS for diabetic retinopathy have been published [15][16][17][18][19], although none report a genome-wide significant signal at 17q25. Of note, four of the previously published studies were conducted in non-European populations (Chinese [17], Taiwanese [18], Japanese [19] and Mexican American [15]), while one was predominantly in patients with type 1 diabetes mellitus [16].…”

Biomarkers in Diabetic Retinopathy

“…GWAS in diabetic retinopathy are emerging, and have suggested several loci related to diabetic retinopathy risk. For example, a Japanese study (<1000 cases and controls) reported associations between the long non-coding (lnc) RNA RP1-90L14 and susceptibility to diabetic retinopathy [281]. These studies are relatively small as measured by GWAS standard (ranging from several hundred to several thousand subjects), do not include optimally characterized subjects, and await validation.…”

SLC2A1 Tag SNPs in Greek Patients with Diabetic Retinopathy and Nephropathy

“…More specifically, the examined genes are likely involved in glucose-induced pathways, the metabolism of glucose and lipids, the inflammatory process, oxidative stress, tissue matrix remodeling, angiogenesis, and vascular endothelial dysfunction, or they are growth factors, cytoskeletal proteins, or parts of the renin-angiotensin aldosterone system (RAAS) [6][7][8][9]. Apart from CGAS, genome-wide association studies (GWAS) and linkage studies on patients with T2DM demonstrate a plausible association between genetic loci and DR or DN [10,11].…”